The epidermal growth factor receptor (EGFR, Erb-B1) belongs to a family of proteins involved in the proliferation of normal and malignant cells. Overexpression of EGFR is found in over 70% of human cancers including without limitation non-small cell lung carcinomas (NSCLC), breast cancers, gliomas, squamous cell carcinoma of the head and neck, and prostate cancer. The EGFR tyrosine kinase (EGFR-TK) reversible inhibitor erlotinib (Tarceva®) is approved by the United States Food and Drug Administration (FDA) for the treatment of NSCLC and advanced pancreatic cancer. Other FDA approved anti-EGFR targeted molecules include gefitinib (Iressa®) and lapatinib.
The response rate of lung cancer tumor shrinkage to erlotinib or gefitinib is about 8-10% and the median time to tumor progression is approximately 2 months. However, lung cancers with somatic mutations in EGFR can be associated with dramatic clinical responses following treatment with geftinib and erlotinib. Somatic mutations identified to date include point mutations in which a single amino acid residue is altered in the expressed protein (e.g. L858R, G719S, G719C, G719A, L861Q), as well as small in frame deletions in exon 19 or insertions in exon 20. Prospective clinical trials treating chemotherapy naïve patients with EGFR mutations with gefitinib or erlotinib have found radiographic response rates ranging from 60-82% and median times to progression of 9.4 to 13.3 months. See Inoue, A. et al., Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. J Clin Oncol 24, 3340-3346 (2006); Sequist, L. V. et al., First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol 26, 2442-2449 (2008). These outcomes are 3- to 4-fold greater than that observed with platin-based chemotherapy (20-30% and 3-4 months, respectively) for advanced NSCLC. Conversely, NSCLC patients with wild type EGFR may have a worse outcome when they received gefitinib compared to chemotherapy as their initial treatment for advanced NSCLC. Thus EGFR mutations can be used to select NSCLC patients for therapy with EGFR TKIs over conventional chemotherapy.
Despite the initial clinical benefits of gefitinib/erlotinib in NSCLC patients harboring EGFR mutations, most if not all patients ultimately develop progressive cancer while receiving therapy on these agents. A secondary EGFR mutation, T790M, can render gefitinib and erlotinib ineffective inhibitors of EGFR kinase activity. The EGFR T790M mutation is found in approximately 50% of tumors (24/48) from patients that acquire resistance to gefitinib or erlotinib. This secondary genetic alteration occurs in the “gatekeeper” residue and in an analogous position to other secondary resistance alleles in diseases treated with kinase inhibitors, e.g., T315I in ABL in imatinib resistant chronic myeloid leukemia (CML).
Another major limitation of current EGFR inhibitors is the development of toxicity in normal tissues. Because ATP affinity of EGFR T790M is similar to wild type EGFR, the concentration of an irreversible EGFR inhibitor required to inhibit EGFR T790M may also effectively inhibit wild type EGFR. The class-specific toxicities of current EGFR kinase inhibitors, e.g., skin rash and diarrhea, are a result of inhibiting wild type EGFR in non-cancer tissues. These toxicities preclude dose escalation of current agents to plasma levels that can effectively inhibit EGFR T790M.
The present invention provides mutant specific EGFR inhibitors that are less effective against wild type EGFR.